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Management of Hepatitis C Infection

Stefan Zeuzem, MD
Program Director
Jordan J. Feld, MD, MPH
Hemant Shah, MD, MScCH HPTE
Released: June 17, 2019

Summary of Key Clinical Studies

The efficacy of treatment for HCV infection varies according to baseline factors, of which HCV genotype and fibrosis stage have the greatest clinical significance. Genotype 1 has been the primary focus for the development of DAAs. Sofosbuvir has antiviral activity against genotypes 1-6. Ledipasvir/sofosbuvir has antiviral activity against genotypes 1-6 but is less potent against genotypes 2 and 3, ombitasvir/paritaprevir/ritonavir plus dasabuvir is active against genotype 1 and 4, whereas dasabuvir is active against genotype 1 only, daclatasvir and sofosbuvir/velpatasvir have pangenotypic antiviral activity, and elbasvir/grazoprevir is active against genotypes 1, 2, 4, 5, and 6 HCV (potency appears lower for genotype 2 HCV).

Ledipasvir/Sofosbuvir

The safety and efficacy of ledipasvir/sofosbuvir was evaluated in a series of randomized phase III trials called ION-1, -2, and -3. All 3 ION trials demonstrated high SVR rates with ledipasvir/sofosbuvir with or without ribavirin in both previously treated and treatment-naive patients with genotype 1 HCV infection (Figure 2). In the ION-1 trial, 865 previously untreated patients (16% with cirrhosis, 12% black, and 67% with genotype 1a infection) were randomized 1:1:1:1 to receive fixed-dose ledipasvir/sofosbuvir with or without ribavirin for 12 or 24 weeks. Rates of SVR at 12 weeks posttreatment (SVR12) were high at ≥ 97% in all 4 treatment arms.[39] Three patients experienced virologic failure, including 1 patient who experienced virologic breakthrough during the ledipasvir/sofosbuvir 24-week treatment course with suspected nonadherence. This patient had an NS5A resistance associated variant at the time of virologic breakthrough but not at baseline. The other 2 patients experienced virologic relapse after completing treatment and both had NS5A RAS at baseline. Among 140 patients with confirmed NS5A RAS at baseline, 96% achieved SVR12. There was no effect of cirrhosis on SVR12 rates in this study.

The ION-2 trial used the same treatment regimens as the ION-1 trial in the treatment of 440 patients (20% with cirrhosis and 79% with genotype 1a infection) who experienced treatment failure with previous peginterferon/ribavirin with or without protease inhibitor therapy.[40] Again, all treatment arms experienced high SVR12 rates with slightly higher rates in both 24-week arms (99%) compared with the 12-week arms (94% without ribavirin and 96% with ribavirin). Overall, 2% of patients experienced virologic relapse after finishing treatment (11/440), all of whom received 12-week treatment durations. Seven of these patients received ledipasvir/sofosbuvir (4 had NS5A RAS at baseline) and 4 received ledipasvir/sofosbuvir plus ribavirin (2 had NS5A RAS at baseline). All patients who achieved SVR12 maintained SVR through 24 weeks posttreatment. Overall, 98% of patients without cirrhosis achieved SVR12, whereas 92% of patients with cirrhosis achieved this outcome.

The ION-3 trial randomized 647 treatment-naive patients with genotype 1 HCV infection without cirrhosis 1:1:1 to receive 8-week courses of ledipasvir/sofosbuvir with or without ribavirin or a 12-week course of ledipasvir/sofosbuvir and found similar SVR12 rates in all treatment arms indicating no additional benefit of the longer treatment course or the addition of ribavirin in this population.[41] Indeed, the 8-week ledipasvir/sofosbuvir treatment course was found to be noninferior to the 12-week course. A total of 23 patients experienced virologic relapse after finishing treatment: 11 from the 8-week ledipasvir/sofosbuvir arm, 9 from the 8-week ledipasvir/sofosbuvir plus ribavirin arm, and 3 from the 12-week ledipasvir/sofosbuvir arm. Patients with confirmed NS5A resistant virus at baseline accounted for 18% (116/647) of patients for whom data were available. Fifteen of the 23 patients who relapsed had NS5A RAS. In a post hoc subanalysis of patients with baseline HCV RNA < 6 million IU/mL in the ION-3 trial, SVR12 rates were 97% with 8 weeks and 96% with 12 weeks of ledipasvir/sofosbuvir treatment.[25] In the 8-week treatment arm, virologic relapse occurred in 2% of patients with baseline HCV RNA < 6 million IU/mL vs 10% in those with baseline HCV RNA ≥ 6 million IU/mL.

No patients in the 12-week treatment arms in the ION-1 or ION-2 trials or in the 8-week ledipasvir/sofosbuvir arm in the ION-3 trial discontinued therapy due to adverse events. The most common adverse events reported were fatigue, headache, nausea, and insomnia (ION-1). The incidence of adverse events was lower in patients not receiving ribavirin.

Figure 2. ION-1, -2, and -3: ledipasvir/sofosbuvir ± ribavirin in genotype 1 HCV.[39-41]

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Following its approval in 2014, 3 large observational studies have found high SVR rates with ledipasvir/sofosbuvir in patients with genotype 1 HCV infection who were treated in real-world settings, outside of clinical trials. In a study of 1597 patients treated at academic and community centers in the TRIO Network, 94% of patients with genotype 1 HCV infection treated with ledipasvir/sofosbuvir and 97% of those treated with ledipasvir/sofosbuvir plus ribavirin achieved SVR12.[36] Factors identified to be significantly associated with decreased likelihood of SVR included prescription of the regimen outside of the FDA-approved label and treatment at an academic center. An examination of data from 2255 patients with genotype 1 HCV infection treated in the HCV-TARGET consortium of medical centers in the United States and Europe also found high SVR12 rates: 96% to 97% among patients treated with ledipasvir/sofosbuvir for 8 or 12 weeks and 95% among those treated for 24 weeks, as well as 97% among patients treated with ledipasvir/sofosbuvir plus ribavirin for 12 weeks and 95% of those receiving the same regimen for 24 weeks.[38] Among 586 patients in this consortium who qualified for the 8-week ledipasvir/sofosbuvir regimen (treatment naive, no cirrhosis, and baseline HCV RNA < 6 million IU/mL), only 255 received an 8-week treatment duration and the remainder were treated for 12 weeks. Similar to the TRIO study, patients with cirrhosis were less likely to achieve SVR. In addition, patients who were receiving PPIs at the outset of treatment also had a lower SVR rate (93.5%) vs patients who were not receiving PPIs at baseline (97.2%). Finally, an examination of data from 4365 patients treated at US Veterans Administration centers found that 91.3% of those treated with ledipasvir/sofosbuvir achieved SVR12.[37] As in the previous 2 studies, patients with cirrhosis at the start of the treatment were less likely to achieve SVR. In this study, black race was also associated with a lower likelihood of SVR vs nonblack race (odds ratio: 0.70; P = .004), but this association was no longer statistically significant when the analysis was limited to patients who completed 12 weeks of therapy. Among patients without cirrhosis and with baseline HCV RNA < 6,000,000 IU/mL, SVR rates were lower with 8 weeks vs 12 weeks of treatment (P = .001 if absence of cirrhosis defined by FIB-4 ≤ 3.25); however, the numeric difference between SVR rates was small at ~ 3%.

Ledipasvir/sofosbuvir has also been evaluated in patients with genotype 4 HCV in the open-label phase IIa SYNERGY trial.[110] Twenty-one patients entered this single-arm study, of whom 38% were treatment experienced, although none had received DAAs before. One third had cirrhosis. All patients received 12 weeks of ledipasvir/sofosbuvir. Ninety-five percent achieved SVR.

Sofosbuvir/Velpatasvir

The efficacy and safety of the fixed-dose sofosbuvir/velpatasvir combination was evaluated in 4 phase III trials (ASTRAL-1, ASTRAL-2, ASTRAL-3, and ASTRAL-4) that enrolled patients with genotype 1, 2, 3, 4, 5, or 6 HCV infection.[111-113] In all 4 trials, SVR rates at 12 weeks posttreatment (SVR12) were higher with sofosbuvir/velpatasvir vs placebo or standard treatment. The ASTRAL-1 trial evaluated a 12-week course of sofosbuvir/velpatasvir in treatment-naive and treatment-experienced patients with chronic genotype 1, 2, 4, 5, or 6 HCV infection.[111] Patients with genotype 1, 2, 4, or 6 HCV infection underwent randomization to receive either sofosbuvir/velpatasvir or placebo, and all 20 patients with genotype 5 HCV infection were given sofosbuvir/velpatasvir because of low genotype 5 enrollment. In the sofosbuvir/velpatasvir arm, 34% had genotype 1a, 19% genotype 1b, 17% genotype 2, 19% genotype 4, 6% genotype 5, and 7% genotype 6 HCV infection, 32% of patients had received previous HCV therapy, 69% had a non-CC IL28B genotype, and 19% had cirrhosis. (Note that outcomes for the subset of patients with cirrhosis in the ASTRAL trials are discussed in a separate section of this module on DAAs in the setting of cirrhosis.) Of the 624 patients receiving at least 1 dose of sofosbuvir/velpatasvir, the SVR12 rate was 99%. Two patients experienced virologic failure after treatment: one who was treatment naive before the trial and another who had experienced previous relapse with peginterferon/ribavirin. NS5A RAS were detected in 42% of patients for whom sequencing data were available and of this subset of patients, the SVR12 rate was 99%. NS5A RAS were detected at the time of relapse in both patients with virologic failure. In the patient with genotype 1a HCV infection, the Y93N variant was detected at relapse but not at baseline and in the other patient with genotype 1b infection, variants Q30L and Q30R were detected at baseline as well as at relapse along with Y93H. All 9% of patients for whom data were available with NS5B RAS at baseline had an SVR. There was no significant difference in adverse events between the sofosbuvir/velpatasvir and placebo groups, and 1 patient receiving the study drug discontinued treatment because of an adverse event.

Similarly, the ASTRAL-2 and ASTRAL-3 trials showed higher SVR12 rates with sofosbuvir/velpatasvir vs sofosbuvir plus ribavirin in patients with genotype 2 or 3 HCV infection, respectively. In both trials, most patients had non-CC IL2B genotype, and many had experienced relapse with previous HCV treatment (~ 14% in ASTRAL-2 and 26% in ASTRAL-3). In the ASTRAL-2 trial, the SVR12 rate with 12 weeks of sofosbuvir/velpatasvir was 99% vs 94% with 12 weeks of sofosbuvir plus ribavirin (P = .02). No patients receiving sofosbuvir/velpatasvir experienced virologic failure. One patient discontinued sofosbuvir/velpatasvir on Day 1 of treatment after receiving 1 dose due to adverse events. In the ASTRAL-3 trial, the SVR12 rate with 12 weeks of sofosbuvir/velpatasvir was 95% vs 80% with 24 weeks of sofosbuvir plus ribavirin (P < .001). In addition, fewer patients experienced virologic failure with sofosbuvir/velpatasvir (4% vs 14%). The higher SVR12 rates with sofosbuvir/velpatasvir were particularly pronounced in patients who had relapsed with previous HCV therapy or with cirrhosis (Figure 6). Among patients with baseline NS5A RAS at baseline (A30K, L31M, and Y93H), 88% had a SVR, and 97% of patients without NS5A RAS at baseline had an SVR.

Sofosbuvir/Velpatasvir/Voxilaprevir

Efficacy and safety data for the fixed-dose combination sofosbuvir/velpatasvir/voxilaprevir derive from 2 phase III trials (POLARIS-1 and POLARIS-4) that enrolled patients with genotype 1-6 or 1-4 HCV infection, respectively.[20] In both trials, SVR rates at 12 weeks posttreatment (SVR12) were higher with sofosbuvir/velpatasvir/voxilaprevir vs placebo or the dual combination sofosbuvir/velpatasvir. The POLARIS-1 trial randomized 150 patients infected with genotype 1 HCV and previously treated with an NS5A inhibitor to a 12-week course of either sofosbuvir/velpatasvir/voxilaprevir or placebo; another 114 patients with genotype 2-6 HCV infection and previous NS5A experience were all given sofosbuvir/velpatasvir/voxilaprevir. In the sofosbuvir/velpatasvir/voxilaprevir arm, 38% had genotype 1a, 17% genotype 1b, 2% genotype 2, 30% genotype 3, 8% genotype 4, < 1% genotype 5, and 2% genotype 6 HCV infection; 61% of patients had received an NS5B polymerase inhibitor with their previous NS5A inhibitor, 82% had a non-CC IL28B genotype, and 46% had compensated cirrhosis. (Note that outcomes for the subset of patients with cirrhosis in the POLARIS trials are discussed in a separate section of this module on DAAs in the setting of cirrhosis.) Of the 263 patients receiving at least 1 dose of sofosbuvir/velpatasvir/voxilaprevir, the SVR12 rate was 96%. Seven patients experienced virologic failure: 1 with suboptimal plasma concentrations of study drugs suggesting nonadherence and 6 with viral relapse after completion of treatment. Treatment-emergent NS5A RAS were detected in the single patient with on-treatment virologic breakthrough (L31L/M and Y93Y/H) and in 1 additional patient experiencing posttreatment relapse (Y93H). The presence of baseline RASs did not affect response to sofosbuvir/velpatasvir/voxilaprevir, however, as 199 of 205 (97%) patients with NS3 or NS5A RASs at baseline achieved SVR12. Similar rates of adverse events occurred in the sofosbuvir/velpatasvir/voxilaprevir and placebo groups, and 1 patient receiving the study drug discontinued treatment because of an adverse event.

Similarly, the POLARIS-4 trial showed a higher SVR12 rate with sofosbuvir/velpatasvir/voxilaprevir vs sofosbuvir/velpatasvir in patients previously treated with DAAs but no NS5A inhibitors.[20] Overall, 163 patients infected with genotype 1-3 HCV were randomized to 12 weeks of triple therapy vs 151 to dual therapy; an additional 19 patients with genotype 4 HCV infection were also allotted to treatment with sofosbuvir/velpatasvir/voxilaprevir. Most patients had a non-CC IL2B genotype and were previously treated with an NS5B polymerase inhibitor; almost one half had compensated cirrhosis. The SVR12 rate with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir was 98% vs 90% with 12 weeks of sofosbuvir/velpatasvir. Only 1 patient receiving sofosbuvir/velpatasvir/voxilaprevir experienced virologic failure, relapsing after treatment; no treatment-emergent RASs were present. All patients with baseline NS3 or NS5A RASs receiving the triple coformulation achieved SVR12. No patients discontinued sofosbuvir/velpatasvir/voxilaprevir, although 1 patient died post treatment from an illicit drug overdose.

Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir

Dasabuvir/ombitasvir/paritaprevir/ritonavir:Ombitasvir/paritaprevir/ritonavir plus dasabuvir with and without ribavirin has been studied in several phase III trials in various genotype 1 HCV–infected populations, including treatment-naive, treatment-experienced, cirrhotic and noncirrhotic patients, as well as in liver transplantation recipients. In addition, ombitasvir/paritaprevir/ritonavir with and without ribavirin has been evaluated in patients with genotype 4 HCV infection, in whom dasabuvir is not active.[114]

Dasabuvir/ombitasvir/paritaprevir/ritonavir:Ombitasvir/paritaprevir/ritonavir plus dasabuvir has demonstrated high SVR in all patient groups evaluated. In the double-blind phase III SAPPHIRE-I trial of 631 previously untreated patients with genotype 1 HCV infection and no cirrhosis, patients were randomized 3:1 to receive ombitasvir/paritaprevir/ritonavir plus dasabuvir plus ribavirin or placebo for 12 weeks.[115] Of the 473 patients receiving the ombitasvir/paritaprevir/ritonavir plus dasabuvir plus ribavirin regimen, 96.2% obtained SVR at 12 weeks posttreatment. This rate was determined to be noninferior and superior to a historical control SVR derived from comparable patients treated with telaprevir plus peginterferon/ribavirin (Figure 3). SVR rates were slightly higher for patients with genotype 1b infection compared with genotype 1a (98.0% vs 95.3%, respectively). SVR rates were high among all other subgroups analyzed by IL28B genotype, race, fibrosis score, and baseline HCV RNA level. Only 1 patient (genotype 1a infection) receiving the 3 DAA regimen had virologic failure and a total of 7 patients relapsed by posttreatment Week 12. All 8 of these patients had at least 1 variant associated with resistance to one of the 3 DAAs.

The double-blind phase III SAPPHIRE-II trial evaluated the efficacy of ombitasvir/paritaprevir/ritonavir plus dasabuvir plus ribavirin in noncirrhotic patients with genotype 1 HCV infection who had previously experienced either a relapse, partial response, or null response with peginterferon/ribavirin.[116] Of the 297 patients who received the 3-DAA regimen, 96.3% achieved SVR at 12 weeks posttreatment. Again, this rate was noninferior and superior to a historical control SVR rate observed in comparable patients receiving telaprevir and peginterferon/ribavirin (Figure 3). SVR rates were similar for patients with genotype 1a and 1b infection (96.0% vs 96.7%, respectively). SVR rates also remained high across all patient subgroups when stratified by prior treatment response: 95.3% with prior relapse, 100% with prior partial response, and 95.2% with prior null response. Seven patients experienced relapse and all reported high adherence to the study protocol. Five of these patients had genotype 1a infection, and a total of 5 patients had at least 1 variant associated with resistance to one of the 3 DAAs.

Figure 3. SAPPHIRE-I and SAPPHIRE-II: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin in noncirrhotic patients with genotype 1 HCV.[115,116]

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The addition of ribavirin to the ombitasvir/paritaprevir/ritonavir plus dasabuvir regimen was further evaluated in 2 phase III trials conducted in noncirrhotic treatment-naive patients with HCV genotype 1a (PEARL-IV) and genotype 1b (PEARL-III) infection.[117] Among patients with genotype 1a infection, SVR rates were higher in the group receiving the 3-DAA regimen with ribavirin (97.0%) compared with those not receiving ribavirin (90.2%). Both 3-DAA regimens were shown to be noninferior and superior to historical SVR rates from patients treated with telaprevir and peginterferon/ribavirin in this genotype 1a population (Figure 4). The ribavirin-free regimen did not, however, meet criteria for noninferiority to the ribavirin-containing regimen. In patients with genotype 1b infection, SVR rates were comparable between the group receiving the ombitasvir/paritaprevir/ritonavir plus dasabuvir regimen with ribavirin and the group receiving the regimen without ribavirin (99.5% vs 99.0%, respectively). SVR rates in both treatment groups in the genotype 1b study were noninferior and superior to the historical SVR rates with use of telaprevir and peginterferon/ribavirin. In addition, SVR rates in patients who did not receive ribavirin were noninferior to those seen in ribavirin-treated patients. A total of 18 patients with genotype 1a infection experienced virologic failure, of whom 16 did not receive ribavirin. Only 1 patient with genotype 1b infection experienced virologic failure and this patient did receive ribavirin.

Figure 4. PEARL-III and PEARL-IV: ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin in noncirrhotic patients with genotype 1 HCV.[117]

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The PEARL-II study evaluated a 12-week course of ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin in noncirrhotic patients with genotype 1b HCV infection who had been treated previously with peginterferon and ribavirin.[118] All 91 patients receiving the ribavirin-free regimen achieved SVR compared with 85 of 88 (97%) receiving the ribavirin-containing regimen.

Dasabuvir/ombitasvir/paritaprevir/ritonavir:Ombitasvir/paritaprevir/ritonavir plus dasabuvir plus ribavirin has also been evaluated in patients with cirrhosis in the phase III TURQUOISE-II study.[119] However, the FDA prescribing information states that ombitasvir/paritaprevir/ritonavir plus dasabuvir is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C).[14] This contraindication is based on reports of hepatic decompensation and liver failure, including some cases requiring liver transplantation or resulting in death among patients receiving ombitasvir/paritaprevir/ritonavir-containing regimens. Patients who experienced these severe outcomes had evidence of advanced cirrhosis before beginning treatment.

Ombitasvir/paritaprevir/ritonavir with and without ribavirin has demonstrated efficacy in patients with genotype 4 HCV (in whom dasabuvir is not active). In the phase IIb PEARL-I study, 86 treatment-naive and 49 treatment-experienced noncirrhotic patients with genotype 4 HCV received ombitasvir/paritaprevir/ritonavir with or without ribavirin for 12 weeks.[114] Treatment-naive patients were randomized to receive or not receive ribavirin, whereas all treatment-experienced patients received the DAA regimen with ribavirin. All patients receiving ribavirin achieved SVR, regardless of treatment experience, compared with 91% of patients who did not receive ribavirin. As with ombitasvir/paritaprevir/ritonavir plus dasabuvir, the FDA labeling information for ombitasvir/paritaprevir/ritonavir indicates that this combination is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C) based on postmarketing reports of apparent drug-induced liver injury among patients receiving ombitasvir/paritaprevir/ritonavir-containing regimens.[16]

In the RUBY-1 trial, 12 weeks of treatment with ombitasvir/paritaprevir/ritonavir plus dasabuvir, with or without ribavirin, was well tolerated in 20 patients with genotype 1 HCV infection and chronic kidney disease, including patients on hemodialysis, and demonstrated an SVR12 rate of 90%.[120]

The single-arm phase IIIb GARNET trial evaluated 8 weeks of treatment with dasabuvir/ombitasvir/paritaprevir/ritonavir:ombitasvir/paritaprevir/ritonavir plus dasabuvir in 163 treatment-naive patients with genotype 1b HCV infection without cirrhosis. The overall SVR12 rate was 98% in this population.[121] It is important to note several features of the study population when considering the high SVR12 rate following only 8 weeks of treatment, including that 96% of patients were of white race, 93% had baseline HCV RNA levels < 6 million IU/mL, and 91% had F0-F2 fibrosis. Among 15 patients with F3 fibrosis, 2 experienced relapse.

To see a summary of guideline recommendations on use of ombitasvir/paritaprevir/ritonavir plus dasabuvir, click here.

Daclatasvir

The safety and efficacy of daclatasvir in combination with sofosbuvir for 12 weeks was evaluated in 152 patients with genotype 3 HCV infection (101 treatment naive; 51 treatment experienced, including 7 patients with previous sofosbuvir experience) in the phase III open-label ALLY-3 trial.[122] SVR rates were 91% for treatment-naive patients and 86% for previously treated patients. The 8 treatment-experienced patients without SVR all experienced virologic relapse. In subgroup analyses, the SVR rate was considerably lower at 63% among the 32 patients with compensated cirrhosis. Treatment-naive patients without cirrhosis experienced a 97% SVR rate vs 94% of noncirrhotic treatment-experienced patients. Five of the 7 patients with previous sofosbuvir failure experienced SVR. No patients in this trial discontinued for adverse events. One serious adverse event deemed unrelated to study therapy was reported (gastrointestinal hemorrhage).

The subsequent ALLY-3+ open-label phase III trial investigated daclatasvir with sofosbuvir and ribavirin for 12 or 16 weeks in 50 patients with genotype 3 HCV infection and advanced fibrosis or compensated cirrhosis.[123] Overall, 45 of the 50 patients (90%) achieved SVR12. Four patients experienced viral relapse and 1 died, all patients with cirrhosis at the beginning of treatment; 3 of the 4 patients with viral relapse had received other treatments prior to the study and all patients with relapse had the NS5A-Y93H resistance associated variant. All of the 14 patients with fibrosis in both the 12-week and 16-week treatment arms achieved SVR12. Among the 36 patients with cirrhosis, the SVR12 rate was 86% (83% in the 12-week arm and 89% in the 16-week group). There were 5 serious adverse events and 1 death. The most common adverse events were insomnia, fatigue, and headache.

Elbasvir/Grazoprevir

A collection of phase II and III trials have evaluated the safety and efficacy of 12- or 16-week coadministration of elbasvir and grazoprevir with or without ribavirin in treatment-naive and treatment-experienced patients with HCV genotype 1, 2, 4, 5 or 6 infection. These trials have demonstrated high SVR rates across patient populations. In the phase III C-EDGE-TN trial, 421 previously untreated patients with genotype 1, 4, or 6 HCV infection (22% cirrhotic, 70% with HCV RNA > 800,000 IU/mL, and 91% with genotype 1 infection) were randomized 3:1 to receive elbasvir/grazoprevir for 12 weeks (immediate treatment) or placebo for 12 weeks followed by elbasvir/grazoprevir for 12 weeks (deferred treatment). The SVR12 rate in the immediate-treatment arm was 95%.[124] Twelve patients relapsed, and 1 patient experienced virologic breakthrough. In genotype 1 and 6 HCV infection, treatment failure was associated with baseline NS5A RAS and treatment-emergent NS3 or NS5A RAS. Although age, sex, race/ethnicity, IL28B status, and cirrhosis did not affect virologic response rates, high baseline HCV RNA levels were associated with significantly lower SVR12 rates. No drug-related serious adverse events or deaths occurred in treated patients, but 3 patients discontinued study treatment for adverse events (palpitations and anxiety in 1 patient and elevated aminotransferases in 2 patients).

In the phase II C-SCAPE trial, 98 treatment-naive, noncirrhotic patients infected with genotype 2, 4, 5, or 6 HCV were randomized to receive 12 weeks of grazoprevir with or without elbasvir and with or without ribavirin. Patients with genotype 2 HCV infection received grazoprevir and ribavirin with or without elbasvir and achieved SVR12 rates of 80% and 73%, respectively.[125] Elbasvir/grazoprevir with or without ribavirin was highly effective in patients with genotype 4 HCV infection, with 19 of 20 patients (95%) achieving SVR12. Atlhough there were few patients with genotypes 5 or 6 HCV infection (n = 8 each), the addition of ribavirin to elbasvir/grazoprevir seemed to benefit patients infected with genotype 5 HCV, increasing the SVR12 rate from 25% to 100%, whereas the SVR12 rate was 75% both with and without ribavirin in patients with genotype 6 HCV infection.

In the phase III C-EDGE TE trial, 420 patients with genotype 1, 4, or 6 HCV infection (35% cirrhotic, 90% with genotype 1 HCV infection) who experienced previous failure of peginterferon/ribavirin were randomized to receive 12 or 16 weeks of elbasvir/grazoprevir with or without ribavirin. Overall SVR12 rates across the 4 treatment arms ranged from 92% to 98%, with the addition of ribavirin numerically increasing efficacy for each of the treatment durations.[126] Elevated HCV RNA levels and NS3 RAS at baseline did not affect virologic efficacy, but genotype 1a HCV–infected patients with baseline NS5A RAS detectable by either population sequencing (25% sensitivity) or next-generation sequencing (15% sensitivity) achieved an SVR12 rate of 68%. In total, 19 patients experienced virologic failure; these events were equivalently distributed across all arms except the 16-week ribavirin-containing regimen, which had none. This arm demonstrated consistently high SVR12 rates across all studied population subgroups.

In the phase II C-SALVAGE trial, 79 patients infected with genotype 1 HCV (38% genotype 1a, 43% cirrhotic) who experienced previous failure of an HCV protease inhibitor (boceprevir, telaprevir, or simeprevir) with peginterferon/ribavirin regimen received 12 weeks of elbasvir/grazoprevir plus ribavirin. The overall SVR12/24 rate for this population was 96%.[127,128] Among patients with baseline NS3 and/or NS5A RAS, the SVR12/24 rate was 92%. Subgenotype and cirrhosis status did not affect virologic response rates. Furthermore, all patients with previous nonvirologic failure (n = 13) achieved SVR12 vs 96% of patients with previous virologic failure (n = 66). The 3 patients experiencing relapse after elbasvir/grazoprevir plus ribavirin had a history of previous virologic failure, and their baseline RAS reemerged at relapse. No serious adverse events or discontinuations were related to treatment.

Glecaprevir/Pibrentasvir

The efficacy and safety of the fixed-dose glecaprevir/pibrentasvir combination was evaluated in 2 phase II trials (SURVEYOR-I and SURVEYOR-II) and 4 phase III trials (ENDURANCE-1, ENDURANCE-2, ENDURANCE-3, and ENDURANCE-4) that enrolled patients with genotype 1, 2, 3, 4, 5, or 6 HCV infection.[129-131] In all 4 phase III trials, SVR rates at 12 weeks posttreatment (SVR12) were ≥ 95%. The ENDURANCE-1 trial compared 8-week vs 12-week courses of glecaprevir/pibrentasvir in 703 noncirrhotic patients with genotype 1 HCV infection.[130] Most patients were treatment naive, had a non-CC IL28B genotype, and lacked baseline NS3 or NS5A polymorphisms. The SVR12 rates for 8-week and 12-week treatment were 99% and 100%, respectively, with all HIV-coinfected patients and patients previously treated with sofosbuvir achieving SVR12. In the 8-week arm, 1 patient experienced on-treatment virologic failure at Day 29.

ENDURANCE-3 was the other phase III trial to compare 8-week vs 12-week durations of glecaprevir/pibrentasvir, this time alongside 12-week daclatasvir plus sofosbuvir, in treatment-naive, noncirrhotic patients with genotype 3 HCV infection.[130] The SVR12 rates were 95% for the 233 patients receiving 12-week glecaprevir/pibrentasvir, 95% for the 157 patients receiving 8-week glecaprevir/pibrentasvir, and 97% for the 115 patients receiving 12-week daclatasvir plus sofosbuvir. Antiviral activity was high across evaluable patients despite the presence of resistance associated polymorphisms at baseline. Thus, both in ENDURANCE-1 and ENDURANCE-3, 8 weeks of glecaprevir/pibrentasvir was noninferior to 12 weeks, and 12 weeks was noninferior to either a historical or an active control. The frequency of adverse events did not greatly differ by treatment duration in these trials, and serious adverse events and discontinuations for adverse events were rare.

ENDURANCE-2 and ENDURANCE-4 examined 12 weeks of glecaprevir/pibrentasvir in noncirrhotic patients with genotype 2 or 4-6 HCV infection, respectively.[131] The SVR12 rate for each trial was 99%, and no patients with genotype 4-6 HCV infection experienced virologic failure.

Similarly, the phase II SURVEYOR-I/II trials demonstrated high SVR12 rates with 8 weeks of glecaprevir/pibrentasvir in noncirrhotic patients with genotype 1-6 HCV infection or 12 weeks with or without ribavirin in genotypes 1-3.[129] Across genotypes, response rates ranged from 97% to 98% for 8-week treatment and from 83% to 100% with 12 weeks. Overall, 2% of patients experienced virologic failure, most of whom were infected with genotype 3a HCV. (Note that outcomes for patients with cirrhosis in the SURVEYOR-I/II and EXPEDITION-1 trials of glecaprevir/pibrentasvir are discussed in a separate section of this module on DAAs in the setting of cirrhosis.)

Direct-Acting Antivirals in Cirrhotic Patients

Ledipasvir/Sofosbuvir. The ION-1 trial evaluated 12-week and 24-week courses of ledipasvir/sofosbuvir with or without ribavirin in 865 treatment-naive patients with genotype 1 HCV infection, including 136 patients (16%) with compensated cirrhosis. Rates of SVR at Week 12 (SVR12) were similar among patients with vs without cirrhosis (Figure 5), although this study was not designed nor powered to specifically evaluate the effect of cirrhosis.[39] In the ION-2 trial also evaluating 12-week and 24-week courses of ledipasvir/sofosbuvir with or without ribavirin in genotype 1 HCV infection, but in treatment-experienced patients (N = 440), 20% of enrolled patients had cirrhosis at baseline. The results demonstrated lower SVR12 rates among patients with vs without cirrhosis in the 12-week treatment arms but not in the 24-week treatment arms (Figure 5).[40] In the 12-week ledipasvir/sofosbuvir arm, the SVR12 rate was 95% in patients without cirrhosis vs 86% in patients with cirrhosis, whereas SVR12 rates were 99% without and 100% with cirrhosis in the 24-week ledipasvir/sofosbuvir arm. Among patients with cirrhosis, SVR12 rates were significantly higher with 24 vs 12 weeks of treatment (P = .007). In addition, the absence of cirrhosis was the only baseline factor identified in a multivariate logistic regression analysis that was significantly associated with SVR12 rates (odds ratio: 5.1; P = .012). In a pooled analysis of phase II/III data from patients with compensated cirrhosis who were treated with ledipasvir/sofosbuvir with or without ribavirin, the SVR12 rate in treatment-experienced patients was lower at 90% when ledipasvir/sofosbuvir was given alone for 12 weeks vs 96% when given in combination with ribavirin for 12 weeks or 98% when administered without ribavirin for 24 weeks.[132]

Results from the SOLAR-1 and -2 studies evaluating ledipasvir/sofosbuvir plus ribavirin in patients with genotype 1 or 4 HCV infection and decompensated cirrhosis have shown high SVR rates (78% to 100% across subgroups) whether given for 12 or 24 weeks.[108,133] Patients generally tolerated therapy well with improvements in MELD score in most patients.

Figure 5. Impact of cirrhosis on SVR12 with ledipasvir/sofosbuvir in patients with genotype 1 HCV infection.[39,40]

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Patients with cirrhosis were included in 3 large observational studies of ledipasvir/sofosbuvir-containing regimens for genotype 1 HCV infection in real-world settings, outside clinical trials. In a study of patients with genotype 1 HCV infection who received ledipasvir-sofosbuvir:ledipasvir/sofosbuvir-based therapy at academic and community centers in the TRIO Network, SVR12 rates were 90.6% among patients with cirrhosis vs 95.9% among patients without cirrhosis.[36] Of the 677 patients with genotype 1 HCV infection and cirrhosis treated with ledipasvir/sofosbuvir or ledipasvir/sofosbuvir plus ribavirin in a separate study involving the HCV-TARGET consortium of medical centers, 93.5% reached SVR12 (89.8% of those with decompensated cirrhosis; 97.4% of those with compensated cirrhosis).[38] In a study of patients treated at US Veterans Administration centers, among those with genotype 1 HCV infection and advanced fibrosis (F3) or cirrhosis, the SVR12 rate was 88% with ledipasvir/sofosbuvir (n = 889) and 90% with ledipasvir/sofosbuvir plus ribavirin (n = 323).[37]

Sofosbuvir/Velpatasvir. The fixed-dose combination of sofosbuvir/velpatasvir is approved for use in patients with genotype 1, 2, 3, 4, 5, or 6 HCV infection with compensated (Child-Pugh A) cirrhosis for 12 weeks and in patients with decompensated cirrhosis (Child-Pugh B and C) for 12 weeks with ribavirin.[27] Patients with compensated cirrhosis were included in the phase III ASTRAL-1, ASTRAL-2, and ASTRAL-3 trials evaluating the safety and effectiveness of sofosbuvir/velpatasvir. In the ASTRAL-1 trial enrolling patients with genotype 1, 2, 4, 5, or 6 HCV infection, 120 of 121 patients with compensated cirrhosis had an SVR12 after sofosbuvir/velpatasvir.[111] In the ASTRAL-2 trial comparing sofosbuvir/velpatasvir with sofosbuvir plus ribavirin, each for 12 weeks, in 266 patients with genotype 2 HCV infection, 14% of patients had compensated cirrhosis. High SVR12 rates were observed in both treatment groups: 99% with sofosbuvir/velpatasvir and 94% with sofosbuvir plus ribavirin.[112] The ASTRAL-3 trial compared a 12-week course of sofosbuvir/velpatasvir with a 24-week course of sofosbuvir plus ribavirin in 552 patients with genotype 3 HCV infection including approximately 30% of patients with compensated cirrhosis. In all subgroups, SVR12 rates were higher with sofosbuvir/velpatasvir, an effect that was more pronounced in patients with cirrhosis as well as patients who had relapsed with previous HCV therapy (Figure 6).

Figure 6. ASTRAL-3: impact of cirrhosis and previous treatment with sofosbuvir/velpatasvir in patients with genotype 3 HCV infection.

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Patients with decompensated cirrhosis were evaluated in the open-label ASTRAL-4 trial comparing sofosbuvir/velpatasvir with or without ribavirin for 12 weeks or sofosbuvir/velpatasvir for 24 weeks in 267 patients with genotype 1-6 HCV infection.[113] All treatment arms showed high SVR12 rates with the highest rate in patients treated with sofosbuvir/velpatasvir plus ribavirin for 12 weeks (94%, n = 87) followed by sofosbuvir/velpatasvir for 24 weeks (86%, n = 90), and sofosbuvir/velpatasvir without ribavirin for 12 weeks (83%, n = 90). Among the 22 patients who experienced virologic failure, 3 received sofosbuvir/velpatasvir plus ribavirin for 12 weeks, 11 received sofosbuvir/velpatasvir without ribavirin for 12 weeks, and 8 received sofosbuvir/velpatasvir for 24 weeks. Patients with genotype 3 HCV infection accounted for the majority of patients who relapsed in all treatment groups. Of the 250 patients with Child-Pugh and MELD scores available posttreatment, 47% had improvement in Child-Pugh score over baseline, 42% had no change, and 11% had worsening scores. Of 223 patients with available data and a baseline MELD score of < 15, 51% had an improvement in MELD score, 22% had no change, and 27% had worsening scores.

Sofosbuvir/Velpatasvir/Voxilaprevir. The fixed-dose combination of sofosbuvir/velpatasvir/voxilaprevir is approved for 12-week retreatment of patients with compensated (Child-Pugh A) cirrhosis and either genotype 1-6 HCV infection and previous NS5A exposure or genotype 1a or 3 HCV infection and previous sofosbuvir exposure.[18] Patients with compensated cirrhosis were included in the phase III POLARIS-1 and POLARIS-4 trials evaluating the safety and efficacy of sofosbuvir/velpatasvir/voxilaprevir (Figure 7). In the POLARIS-1 trial enrolling patients with genotype 1-6 HCV infection and previous NS5A inhibitor experience, 93% of patients with compensated cirrhosis had an SVR12 after sofosbuvir/velpatasvir/voxilaprevir.[20] All 7 of the patients experiencing virologic failure in this trial had compensated cirrhosis. In the POLARIS-4 trial comparing sofosbuvir/velpatasvir/voxilaprevir with sofosbuvir/velpatasvir, each for 12 weeks in DAA-experienced patients who had not received a previous NS5A inhibitor, 46% of patients receiving triple therapy had compensated cirrhosis. A higher SVR12 was observed with sofosbuvir/velpatasvir/voxilaprevir vs sofosbuvir/velpatasvir (98% vs 86%, respectively), and the 1 patient who experienced virologic failure on triple therapy had cirrhosis.[20]

Figure 7. Impact of cirrhosis on SVR12 with sofosbuvir/velpatasvir/voxilaprevir therapy in NS5A inhibitor–experienced or sofosbuvir-experienced patients.[20]

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Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir. Dasabuvir/ombitasvir/paritaprevir/ritonavir:Ombitasvir/paritaprevir/ritonavir plus dasabuvir is approved for use in patients with genotype 1 HCV infection with cirrhosis in the United States.[14] A 24-week treatment course in combination with ribavirin is indicated for cirrhotic patients with genotype 1a HCV infection, although 12 weeks may be considered for some patients based on prior treatment experience. A 12-week treatment course in combination with ribavirin is indicated for cirrhotic patients with genotype 1b HCV infection. The FDA prescribing information states that ombitasvir/paritaprevir/ritonavir plus dasabuvir and ombitasvir/paritaprevir/ritonavir are contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C).[14,16] This contraindication is based on reports of hepatic decompensation and liver failure, including some cases requiring liver transplantation or resulting in death among patients receiving ombitasvir/paritaprevir/ritonavir-containing regimens. Patients who experienced these severe outcomes had evidence of advanced cirrhosis before beginning treatment. As a result of these reports, including some cases of rapid-onset liver injury in patients with compensated cirrhosis, the AASLD/Infectious Diseases Society of America guidance panel advised that healthcare providers should discuss the low but potential risk of drug-induced liver injury with patients who have compensated cirrhosis and are considering a ombitasvir/paritaprevir/ritonavir-based regimen.[54] The guidance panel further notes that patients with compensated cirrhosis who are treated with ombitasvir/paritaprevir/ritonavir require close monitoring of total and direct bilirubin and transaminase levels every 1-2 weeks during the first 4 weeks of therapy for early detection of drug-induced liver injury and that such patients should be educated on the importance of reporting any symptoms, including jaundice, weakness, fatigue. Ombitasvir/paritaprevir/ritonavir-based regimens should be immediately discontinued if drug-induced liver injury is detected.

The open-label, phase III TURQUOISE-II trial evaluated the efficacy of ombitasvir/paritaprevir/ritonavir plus dasabuvir plus ribavirin in both previously treated and untreated patients with genotype 1 HCV infection and cirrhosis, as determined by liver biopsy (Metavir score > 3, Ishak score > 4) or FibroScan (≥ 14.6 kPa within 6 months).[119] In total, 380 patients were randomized to receive either 12 or 24 weeks of treatment. High rates of SVR were seen in both treatment arms—91.8% with the 12-week regimen and 95.9% with the 24-week regimen—and this difference did not reach statistical significance (Figure 8). Both the 12-week and 24-week regimens were found to be noninferior and superior to historic control rates derived from comparable patients treated with telaprevir and peginterferon/ribavirin. Among the patients who had received prior treatment, SVR rates were generally high. However, multivariate logistic-regression analysis found that prior null responses to peginterferon/ribavirin treatment, genotype 1a HCV infection, and history of injection drug use were associated with a lower likelihood of achieving SVR. Thirteen patients receiving 12 weeks of treatment and 4 patients receiving 24 weeks of treatment experienced virologic failure, of which 15 of these patients had at least 1 resistance associated variant to 1 or more components of the 3-DAA regimen. Data from a subgroup analysis of TURQUOISE-II suggested that patients with genotype 1a HCV infection and platelet counts < 100,000 x cells/mm3 and/or albumin levels < 3.5 g/dL may benefit from receiving an extended treatment duration of 24 weeks rather than 12 weeks.[134]

Figure 8. TURQUOISE-II: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin in genotype 1 HCV with cirrhosis.[119]

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Elbasvir/Grazoprevir. Elbasvir/grazoprevir is approved for use in patients with genotype 1 or 4 HCV infection with compensated cirrhosis (Child-Pugh A) in the United States.[17] However, this coformulation is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C). Treatment for patients with compensated cirrhosis is the same as for patients without cirrhosis, with a duration of 12 or 16 weeks, with or without ribavirin depending on treatment experience, HCV genotype and subtype, and presence of NS5A polymorphisms (in genotype 1a HCV infection only).

The phase III C-EDGE-TN trial evaluated 12 weeks of elbasvir/grazoprevir in 421 treatment-naive patients with genotype 1, 4, or 6 HCV infection, including 92 patients (22%) with compensated cirrhosis. Rates of SVR12 were similar among patients with vs without cirrhosis at 97% vs 94%, respectively.[124] In the phase III C-EDGE TE trial evaluating 12 or 16 weeks of elbasvir/grazoprevir with or without ribavirin in 420 patients with genotype 1, 4, or 6 HCV infection who experienced previous failure of peginterferon/ribavirin, 35% of enrolled patients had cirrhosis at baseline. The results demonstrated SVR12 rates of 93.8% in patients with cirrhosis who received 12 or 16 weeks of elbasvir/grazoprevir, regardless of the inclusion of ribavirin, vs 96.6% in patients without cirrhosis.[126]

The phase II C-SALVAGE trial enrolled 79 patients with genotype 1 HCV infection who experienced previous failure of boceprevir, telaprevir, or simeprevir in combination with peginterferon/ribavirin, including 34 patients (43%) with cirrhosis. All patients were treated with 12 weeks of elbasvir/grazoprevir plus ribavirin, for an overall SVR12/24 rate of 96%. Among patients with cirrhosis, the SVR12/24 rate was similar at 94%.

Glecaprevir/Pibrentasvir. Glecaprevir/pibrentasvir is approved for the treatment of patients with genotype 1-6 HCV infection and compensated cirrhosis (Child-Pugh A) in the United States.[21] A 12-week treatment course is indicated for treatment-naive cirrhotic patients infected with any HCV genotype as well as for NS3/4-experienced patients with genotype 1 HCV infection and those previously treated with interferon, peginterferon, ribavirin, and/or sofosbuvir who have genotype 1, 2, 4, 5, or 6 HCV infection. A longer, 16-week treatment course is indicated for cirrhotic patients with previous NS5A exposure and genotype 1 HCV infection or those infected with genotype 3 HCV who were previously treated with interferon, peginterferon, ribavirin, and/or sofosbuvir. Any length of regimen use is either not recommended or contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C).[21]

The open-label phase II SURVEYOR-I/II trials evaluated the efficacy of glecaprevir/pibrentasvir with or without ribavirin in both previously treated and treatment-naive patients with genotype 1 or 3 HCV infection and compensated cirrhosis, as determined by liver biopsy (Metavir score > 3 or Ishak score > 4; FibroTest ≥ 0.75 and APRI > 2; or FibroScan ≥ 14.6 kPa within 6 months).[135] In total, 27 patients with genotype 1 received 12 weeks of glecaprevir/pibrentasvir, whereas 55 patients with genotype 3 were randomized to receive either the coformulation alone or with ribavirin. Glecaprevir/pibrentasvir duration was extended to 16 weeks in 4 treatment-experienced patients infected with genotype 3 HCV based on feedback from the FDA. High rates of SVR were seen in all treatment groups—96% in genotype 1, 96% without ribavirin in genotype 3, and 100% with ribavirin in genotype 3 (Figure 9). One treatment-naive patient with genotype 1a HCV infection and 1 treatment-experienced patient with genotype 3a HCV infection experienced virologic failure on 12-week, ribavirin-free glecaprevir/pibrentasvir. Both patients developed a treatment-emergent NS5A RAS at failure (Y93N and M28G, respectively). SVR rates remained high regardless of the presence of baseline RASs.

Figure 9. Impact of cirrhosis, genotype, and treatment experience on SVR12 with glecaprevir/pibrentasvir with or without ribavirin.[135,136]

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The single-arm, open-label phase III EXPEDITION-1 trial assessed 12-week glecaprevir/pibrentasvir in patients with genotype 1, 2, 4, 5, or 6 HCV infection and compensated cirrhosis.[136] Of 146 enrolled, most patients were treatment naive, but 25% had previously received regimens containing interferon, peginterferon, ribavirin, or sofosbuvir. SVR occurred in 145 of 146 (99%) patients at posttreatment Week 12 (Figure 9). One patient with genotype 1a HCV infection and previous failure of peginterferon plus ribavirin relapsed at posttreatment Week 8; treatment-emergent Q30R-H58D occurred in NS5A. As in SURVEYOR-I/II, SVR rates were unaffected by baseline NS3 or NS5A polymorphisms.

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